Pretreatment Carcinoembryonic Antigen Level Serves as a Potential Biomarker to Guide Adjuvant Radiotherapy in pT4N+ Colon Cancer Patients

The survival benefit of adjuvant radiotherapy in T4 colon cancer (CC) remains controversial, with conflicting results reported in the literature. This study aimed to explore the relationship between pretreatment carcinoembryonic antigen (CEA) level and overall survival (OS) of pT4N+ CC patients treated with adjuvant radiotherapy. Data of pT4N+ CC patients who received curative surgery between 2004 and 2015 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. The primary outcome was OS, and subgroup analysis was conducted according to pretreatment CEA level. A total of 8763 patients were eligible for our study. In the CEA-normal group, 151 patients received adjuvant radiotherapy, while 3932 patients did not. In the CEA-elevated group, 212 patients received adjuvant radiotherapy, while 4468 patients did not. In general, adjuvant radiotherapy was associated with better OS in pT4N+ CC patients (HR = 0.846, 95% CI = 0.733–0.976, P = 0.022). Intriguingly, only patients with an elevated pretreatment CEA level gained a survival benefit from adjuvant radiotherapy (HR = 0.782; 95% CI = 0.651–0.939; P = 0.008) while those with a normal pretreatment CEA level did not (HR = 0.907; 95% CI = 0.721–1.141; P = 0.403). Multivariable Cox regression analysis demonstrated that adjuvant radiotherapy was an independent protective factor in pT4N+ CC patients with an elevated pretreatment CEA level. Pretreatment CEA levels could serve as a potential biomarker to screen pT4N+ CC patients who would benefit from adjuvant radiotherapy.


Introduction
Colorectal cancer (CRC) is the third most prevalent malignant tumor and the second most common cause of cancer-related death worldwide [1]. Surgery-based comprehensive therapy is the gold standard for the treatment of stage III disease. Despite the fact that radiotherapy has been widely adopted for locally advanced rectal cancer, the role of radiotherapy in the management of colon cancer (CC) is largely undefned. About 10% to 15% of CC patients are diagnosed with T4 disease that penetrates the colonic serosa. Te oncological outcomes remain poor for T4 CC although these patients receive multivisceral resection and adjuvant chemotherapy or radiotherapy [2]. Several retrospective studies evaluated the value of adjuvant radiotherapy in T4 CC patients, with conficting results [3][4][5][6][7]. A recent study indicated that adjuvant radiotherapy did not improve survival in T4 CC using the National Cancer Database and the Surveillance, Epidemiology, and End Results (SEER) [8]. Defnitely, it is unreasonable to adopt adjuvant radiotherapy for all T4 CC patients, especially those without lymph node involvement. Terefore, it is necessary to identify a subgroup that benefts more from adjuvant radiotherapy.
Carcinoembryonic antigen (CEA) is the most widely applied marker in the follow-up of CRC, and an elevated CEA level often indicates tumor relapse and poor prognosis [9][10][11]. Furthermore, CEA level has been found to be a potential biomarker guiding neoadjuvant or adjuvant therapy [12,13]. Our previous study also evaluated the guiding role of an elevated pretreatment serum CEA level for adjuvant chemotherapy in stage IIA CC [14]. In our present study, we would like to determine whether pretreatment CEA level could serve as a potential biomarker to guide adjuvant radiotherapy in pT4N+ CC patients.

Patient Selection.
Tis is a retrospective cohort study. pT4N + M0 CC (AJCC 7th edition) patients who received curative surgery and had the defnite data regarding pretreatment CEA status and adjuvant radiotherapy were recruited from the SEER database (2004)(2005)(2006)(2007)(2008)(2009)(2010)(2011)(2012)(2013)(2014)(2015). Te SEER database (https://seer.cancer.gov/seerstat/) was an authoritative and public source of information on cancer incidence, mortality, prevalence, lifetime risk statistics, and survival among 26% of the population in 18 cancer registries in the United States. In general, the inclusion criteria were detailed as follows: patients were diagnosed with pT4N + M0 CC; patients did not receive neoadjuvant radiotherapy; curative surgery was performed; patients had a defnite CEA status; survival data were available. Te exclusion criteria were detailed as follows: patients with distant metastases; patients who received both neoadjuvant radiotherapy and adjuvant radiotherapy. Te following pathological and survival data were collected: histologic type, grade, tumor size, node stage, radiotherapy, pretreatment serum CEA level, and survival data. Overall survival (OS) was regarded as a primary endpoint. OS was defned as the time from the date of diagnosis to the date of death.

Statistical Analysis.
Te diferences of categorical variables between two groups were determined by χ 2 test. Te Kaplan-Meier (K−M) method and the univariate Cox regression model were utilized for comparison of the survival diference between the two groups with a log-rank test. A multivariate Cox regression model was used to seek for the independent prognostic factors. All statistical analyses were performed using SPSS 25.0.

Patients' Characteristics.
A total of 8763 patients were eligible for our study. 363 patients received adjuvant radiotherapy, and 8400 patients did not receive adjuvant radiotherapy. In CEA-normal group, 151 patients received adjuvant radiotherapy, while 3932 patients did not. In the CEA-elevated group, 212 patients received adjuvant radiotherapy, while 4468 patients did not. Te baseline characteristics between two groups stratifed by CEA status are summarized in Table 1.

Association of Pretreatment CEA Status and Adjuvant
Radiotherapy in Predicting Prognosis. Next, we wonder whether serum CEA status had a guiding role in predicting a survival beneft from adjuvant radiotherapy. We found  (Figure 2(a)).

Discussion
In the current study, we demonstrated that pT4N + M0 CC patients could beneft from adjuvant radiotherapy. Especially, only pT4N + M0 CC patients with elevated pretreatment CEA level obtained a survival beneft from adjuvant radiotherapy while those with normal pretreatment CEA level did not. Further multivariable Cox regression analysis demonstrated that adjuvant radiotherapy was an independent protective factor in pT4N+ CC patients with an elevated pretreatment CEA level. Tere has been controversy over adopting adjuvant radiotherapy for locally advanced CC. Despite this, current NCCN guidelines recommend receipt of radiotherapy for T4 CC patients. In earlier research, postoperative radiotherapy appeared to improve local control in T4 CC patients [3,4]. In the modern chemotherapy era, evidence indicated that the benefts of locoregional control and enhanced disease-free survival were still observed for T4 colon cancer treatment with adjuvant radiotherapy [5]. A prospective, randomized controlled trial (Intergroup-0130) evaluated the role of radiotherapy in resected CC but failed to meet its accrual goals [6]. Recently, Margalit et al. reported that postoperative radiation did not improve overall survival in individuals with pathologic stage T4 colon cancer using the National Cancer Database [7]. Specifcally, T4b colon tumors also did not obtain a survival beneft from adjuvant radiotherapy, regardless of surgical margin status. Similarly, another large comparative study also demonstrated that T4 CC patients did not beneft from adjuvant radiotherapy using the National Cancer Database and the Surveillance, Epidemiology, and End Results Program [8]. It is interesting to note whether a specifc subgroup is likely to beneft from adjuvant radiotherapy. Adjuvant radiotherapy is currently recommended for node-positive middle and low-grade rectal cancer, which does not receive neoadjuvant radiotherapy to reduce the local recurrence rate. We wondered whether adjuvant radiotherapy improved survival in pT4 node-positive CC patients. Our study demonstrated that adjuvant radiotherapy resulted in a decreased risk of mortality. Consistently, Huang et al. found that adjuvant radiotherapy could decrease CC-related mortality risk by nearly 30% in the T4N2M0 subgroup, which was signifcantly higher than the 11.51% of the general T4 population [15].
Pretreatment CEA level has been identifed as a predictive biomarker of treatment response. Wang et al. found that the pretreatment CEA level may be considered a potential biomarker to select locally advanced rectal cancer patients who would beneft from preoperative radiotherapy [16]. Huang et al. reported that pretreatment serum CEA level may serve as a promising biomarker guiding adjuvant chemotherapy in rectal cancer patients with ypT3N0M0 following neoadjuvant radiotherapy [17]. Tese studies indicated that the pretreatment CEA level could be used as a determinant for adopting neoadjuvant radiotherapy. Although adjuvant radiotherapy for pT4 node-positive patients ofers a survival advantage, it is unreasonable to adopt adjuvant radiotherapy for all pT4 node-positive CC patients in terms of therapeutic toxicity and treatment cost. It is valuable to identify a subgroup that benefts more from adjuvant radiotherapy. Intriguingly, our results indicated that adjuvant radiotherapy would only beneft pT4N+ CC patients with an elevated pretreatment CEA level. Tis fnding suggested that pretreatment CEA level could be used as a potential biomarker to select pT4N+ CC patients who would gain the long-term survival beneft from adjuvant radiotherapy. To the best of our knowledge, this is the frst time in the literature that we have found a biomarker to guide adjuvant radiotherapy in T4N+ CC patients. It is particularly important for pT4N+ CC patients with a normal pretreatment CEA level to avoid the side efects of radiotherapy without compromising oncological outcomes. However, there are several inevitable limitations to the present study. First, selection bias is hard to avoid in a retrospective analysis. Second, data regarding serum CEA level after surgery were unavailable in the SEER database. Besides that, data regarding the circumferential resection margin and tumor deposits in the SEER database were

Conclusions
In conclusion, pretreatment CEA level could serve as a potential biomarker to identify pT4N+ CC patients who benefted from adjuvant radiotherapy.

Data Availability
Te data that support the fndings of this study are available from the corresponding author upon reasonable request.

Disclosure
Te funders had no role in the study design, data collection and analysis, decision to publish, or manuscript preparation.

Conflicts of Interest
Te authors declare that they have no conficts of interest.